The exon 14 JAK2 V617F mutation has been well established as a driver mutation in polycythemia vera (PV) and other myeloproliferative neoplasms. JAK2 exon 12 mutations have also been implicated in PV, although patients with these mutations may show isolated erythrocytosis. Recently additional JAK2point mutations have been described-all in regions encoding the pseudokinase domain that regulates the tyrosine kinase activity of JAK2. We present a case of a patient with erythrocytosis and an exon 13 G571S mutation, and discuss the putative role of this mutation in myeloproliferative neoplasms...

BACKGROUND: The association between hemoglobin (Hb) levels and mortality in patients with ST-segment elevation myocardial infarction (STEMI) remains controversial. The purpose of this study was to examine the mortality among STEMI patients with anemia or erythrocytosis, and further establish the relationship between mortality and the increment of Hb level. METHODS: Between 2006 and 2012, 951 consecutive patients with STEMI undergoing primary percutaneous coronary intervention in a medical center in Northern Taiwan were enrolled in our study, including 535 patients with normal Hb level, 148 with anemia (male Hb ≤ 13 g/dl, female ≤ 12) and 268 with erythrocytosis (male Hb ≥ 16, female ≥ 15)...

Erythrocytosis is mainly driven by erythropoietin, which is regulated by hypoxia-inducible factor (HIF). Mutations in HIF prolyl 4-hydroxylase 2 (HIF-P4H-2/PHD2/EGLN1), the major downregulator of HIFα subunits, are found in familiar erythrocytosis, and large-spectrum conditional inactivation of HIF-P4H-2 in mice leads to severe erythrocytosis. Although bone marrow is the primary site for erythropoiesis, spleen remains capable for extramedullary erythropoiesis. We studied HIF-P4H-2 deficient mice (Hif-p4h-2(gt/gt)) which show slightly induced erythropoiesis upon aging despite non-increased erythropoietin levels, and identified spleen as the site of extramedullary erythropoiesis...

: Erythrocytosis is a common paraneoplastic syndrome associated with hepatocellular carcinoma (HCC). Although increased erythropoietin (EPO) is found in these patients, the clinical significance and molecular mechanisms underlying this observation are unclear. Here we demonstrated an inverse relationship between EPO production and overall prognosis in our cohort of 664 patients as well as in data from The Cancer Genome Atlas (TCGA). In the subset of HCC patients with erythrocytosis, we identified somatic mutations of mitochondrial DNA, resulting impairment of respiratory metabolism, which sequentially led to depletion of α-ketoglutarate, stabilization of hypoxia inducible factor-α and expression of target genes such as EPO...

Erythrocytosis is a rare disorder characterized by increased red cell mass and elevated hemoglobin concentration and hematocrit. Several genetic variants have been identified as causes for erythrocytosis in genes belonging to different pathways including oxygen sensing, erythropoiesis and oxygen transport. However, despite clinical investigation and screening for these mutations, the cause of disease cannot be found in a considerable number of patients, who are classified as having idiopathic erythrocytosis...

High oxygen affinity hemoglobins are responsible for rare and heterogeneous autosomic dominant genetic diseases. They cause pure erythrocytosis, sometimes accountable for hyperviscosity and thrombosis, or hemolysis. Differential diagnoses must be first ruled out. The diagnosis is based on the identification of a decreased P50, and their possible characterization by cation exchange-high performance liquid chromatography and capillary electrophoresis. Finally, genetic studies of the responsible globin chain gene will confirm the mutation...

The impact of cerebral Epo in the regulation of the hypercapnic ventilatory response (HcVR) is controversial. While we reported that cerebral Epo does not affect the central chemosensitivity in C57Bl6 mice receiving an intracisternal injection of sEpoR (the endogenous antagonist of Epo), a recent study in transgenic mice with constitutive high levels of human Epo in brain and circulation (Tg6) and in brain only (Tg21), showed that Epo blunts the HcVR, maybe by interacting with central and peripheral chemoreceptors...

Secondary polycythemia, a disease characterized by a selective increase in circulating mature erythrocytes, is caused by enhanced erythropoietin (Epo) concentrations triggered by hypoxia-inducible factor-2α (HIF-2α). While mechanisms of hypoxia-dependent stabilization of HIF-2α protein are well established, data regarding oxygen-independent regulation of HIF-2α are sparse. In this study, we generated a novel transgenic mouse model, in which biglycan was constitutively overexpressed and secreted by hepatocytes (BGN (Tg)), thereby providing a constant source of biglycan released into the blood stream...

BACKGROUND: Testosterone deficiency (hypogonadism) is common among men undergoing haemodialysis, but its clinical implications are not well characterized. Testosterone is an anabolic hormone that induces erythrocytosis and muscle synthesis. We hypothesized that testosterone deficiency would be associated with low muscle mass, physical inactivity and higher dosages of erythropoietin-stimulating agents (ESA). METHODS: Single-center cross-sectional study of 57 male haemodialysis patients...

We report the first patient to develop ALL with a fusion gene of the erythropoietin receptor (EPOR) with immunoglobulin heavy chain (IgH) 22 years after a diagnosis of secondary erythrocytosis with unknown etiology. The IgH-EPOR rearrangement is known to induce increased expression of EPOR, and activates EPO-associated signal pathways by exogenous EPO stimulation, resulting in the increased proliferation and survival of IgH-EPOR-positive leukemic cells. Interestingly, this case may provide supporting the possibility that IgH-EPOR-positive ALL has a growth advantage under sustained high concentrations of EPO...

BACKGROUND: Mobile intra-aortic thrombus without atherosclerosis, aneurysm, or congenital coagulopathy is very rare, and there are few reports especially in young or middle-aged patients. Furthermore, there are presently no established guidelines or common strategies for the treatment of mobile intra-aortic thrombus. In this case report, we describe the first case of intra-aortic thrombus caused by secondary erythrocytosis and describe the recommended treatment strategy for intra-aortic thrombus...

Erythropoiesis requires large amounts of iron for hemoglobin synthesis, which is mainly provided by macrophages and the intestines in a transferrin (Tf)-bound form. Bone marrow erythroblasts incorporate Tf through endocytosis, which is mediated by transferrin receptor 1 (TFR1). Recently, human TFR1, aside from its role as a Tf receptor, was also found to be a receptor for the H-subunit of ferritin (FTH). In humans, hematopoietic erythroid precursor cells express high levels of TFR1 and specifically take up the FTH homopolymer (H-ferritin)...

Patients with von Hippel-Lindau (VHL) disease harbor a germline mutation in the VHL gene leading to the development of several tumor types including clear cell renal cell carcinoma (ccRCC). In addition, the VHL gene is inactivated in over 90% of sporadic ccRCC cases. 'Clear cell' tumors contain large, proliferating cells with 'clear cytoplasm', and a reduced number of cilia. VHL inactivation leads to the stabilization of hypoxia inducible factors 1a and 2a [HIF1a and HIF2a (HIF2a is also known as EPAS1)] with consequent up-regulation of specific target genes involved in cell proliferation, angiogenesis and erythropoiesis...

We have recently demonstrated that the transcription factor nuclear factor-erythroid 2, which is critical for erythroid maturation and globin gene expression, plays an important role in the pathophysiology of myeloproliferative neoplasms. Myeloproliferative neoplasm patients display elevated levels of nuclear factor-erythroid 2 and transgenic mice overexpressing the transcription factor develop myeloproliferative neoplasm, albeit, surprisingly without erythrocytosis. Nuclear factor-erythroid 2 transgenic mice show both a reticulocytosis and a concomitant increase in iron deposits in the spleen, suggesting both enhanced erythrocyte production and increased red blood cell destruction...

Age-related macular degeneration (AMD), affecting the retinal pigment epithelium (RPE), is the leading cause of blindness in middle-aged and older people in developed countries. Genetic and environmental risk factors have been identified, but no effective cure exists. Using a mouse model we show that a transmembrane prolyl 4-hydroxylase (P4H-TM), which participates in the oxygen-dependent regulation of the hypoxia-inducible factor (HIF), is a potential novel candidate gene for AMD. We show that P4h-tm had its highest expression levels in the mouse RPE and brain, heart, lung, skeletal muscle and kidney...

An absolute erythrocytosis is present when the red cell mass is greater than 125 % of the predicted value for sex and body mass. It can have a primary or secondary and congenital or acquired cause. New causes particularly congenital continue to be discovered and investigated. Investigation for the cause starts with repeat and confirmation of the raised hemoglobin and measurement of an erythropoietin level to indicate whether to pursue primary or secondary causes and then further investigations as appropriate...

The 8p11 myeloproliferative syndrome (EMS), also known as 8p11 myeloproliferative neoplasm (8p11 MPN), is a collection of rare hematologic malignancies that are associated with fusion genes involving the tyrosine kinase receptor gene FGFR1 in chromosome 8p11. The entity is an aggressive disease with a high rate of transformation to acute myeloid leukemia (AML) and pathologically characterized by its associated eosinophilia. In this study, we reported a distinctive EMS case featuring an in-frame ZMYM2-FGFR1 fusion gene identified by next-generation sequencing technology (NGS)...